title: Urate-induced acute renal failure and chronic inflammation in liver-specific Glut9 knockout mice.
abstract: Plasma urate levels are higher in humans than rodents (240-360 vs. ∼30 μM) because humans lack the liver enzyme uricase. High uricemia in humans may protect against oxidative stress, but hyperuricemia also associates with the metabolic syndrome, and urate and uric acid can crystallize to cause gout and renal dysfunctions. Thus, hyperuricemic animal models to study urate-induced pathologies are needed. We recently generated mice with liver-specific ablation of Glut9, a urate transporter providing access of urate to uricase (LG9KO mice). LG9KO mice had moderately high uricemia (∼120 μM). To further increase their uricemia, here we gavaged LG9KO mice for 3 days with inosine, a urate precursor; this treatment was applied in both chow- and high-fat-fed mice. In chow-fed LG9KO mice, uricemia peaked at 300 μM 2 h after the first gavage and normalized 24 h after the last gavage. In contrast, in high-fat-fed LG9KO mice, uricemia further rose to 500 μM. Plasma creatinine strongly increased, indicating acute renal failure. Kidneys showed tubule dilation, macrophage infiltration, and urate and uric acid crystals, associated with a more acidic urine. Six weeks after inosine gavage, plasma urate and creatinine had normalized. However, renal inflammation, fibrosis, and organ remodeling had developed despite the disappearance of urate and uric acid crystals. Thus, hyperuricemia and high-fat diet feeding combined to induce acute renal failure. Furthermore, a sterile inflammation caused by the initial crystal-induced lesions developed despite the disappearance of urate and uric acid crystals.
authors.affiliation: Mouse Metabolic Facility of the Cardiomet Center, University Hospital, Lausanne, Switzerland.
authors.forename: Frederic
authors.initials: F
authors.lastname: Preitner
authors.forename: Alexandra
authors.initials: A
authors.lastname: Laverriere-Loss
authors.forename: Salima
authors.initials: S
authors.lastname: Metref
authors.forename: Anabela
authors.initials: A
authors.lastname: Da Costa
authors.forename: Catherine
authors.initials: C
authors.lastname: Moret
authors.forename: Samuel
authors.initials: S
authors.lastname: Rotman
authors.forename: Dominique
authors.initials: D
authors.lastname: Bazin
authors.forename: Michel
authors.initials: M
authors.lastname: Daudon
authors.forename: Christophe
authors.initials: C
authors.lastname: Sandt
authors.forename: Arnaud
authors.initials: A
authors.lastname: Dessombz
authors.forename: Bernard
authors.initials: B
authors.lastname: Thorens
mesh_terms: D058186:Acute Kidney Injury / Q000139:chemically induced*; D000818:Animals; D003460:Crystallization; D059305:Diet, High-Fat; D051246:Glucose Transport Proteins, Facilitative / Q000172:deficiency*; D006863:Hydrogen-Ion Concentration; D033461:Hyperuricemia / Q000097:blood* / Q000209:etiology; D007249:Inflammation / Q000139:chemically induced; D007288:Inosine / Q000378:metabolism; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D027361:Organic Anion Transporters / Q000172:deficiency; D014527:Uric Acid / Q000097:blood; D014556:Urine / Q000502:physiology
chemical_list: D051246:Glucose Transport Proteins, Facilitative; D027361:Organic Anion Transporters; C498775:Slc2a9 protein, mouse; C103862:urate transporter; D014527:Uric Acid; D007288:Inosine
keywords: SLC2A9; acute renal failure; crystal; glucose transporter 9; sterile inflammation; urate